Current Pharmaceutical Design - Volume 22, Issue 21, 2016

Background: Polypharmacology, defined as the modulation of multiple proteins rather than a single target to achieve a desired therapeutic effect, has been gaining increasing attention since 1990s, when industries had to withdraw several drugs due to their adverse effects, leading to permanent injuries or death, with multi-billiondollar legal damages. Therefore, if up to then the “one drug one target” paradigm had seen many researchers interest focused on the identification of selective drugs, with the strong expectation to avoid adverse drug reactions (ADRs), very recently new research strategies resulted more appealing even as attempts to overcome the decline in productivity of the drug discovery industry. Methods: Polypharmacology consists of two different approaches: the former, concerning a single drug interacting with multiple targets related to only one disease pathway; the latter, foresees a single drug’s action on multiple targets involved in multiple disease pathways. Both new approaches are strictly connected to the discovery of new feasible off targets for approved drugs. Results: In this review, we describe how the in silico facilities can be a crucial support in the design of polypharmacological drug. The traditional computational protocols (ligand based and structure based) can be used in the search and optimization of drugs, by using specific filters to address them against the polypharmacology (fingerprints, similarity, etc.). Moreover, we dedicated a paragraph to biological and chemical databases, due to their crucial role in polypharmacology. Conclusion: Multitarget activities provide the basis for drug repurposing, a slightly different issue of high interest as well, which is mostly applied on a single target involved in more than one diseases. In this contest, computational methods have raised high interest due to the reached power of hardware and software in the manipulation of data.

Background: Virtual Screening methodologies have emerged as efficient alternatives for the discovery of new drug candidates. At the same time, ensemble methods are nowadays frequently used to overcome the limitations of employing a single model in ligand-based drug design. However, many applications of ensemble methods to this area do not consider important aspects related to both virtual screening and the modeling process. During the application of ensemble methods to virtual screening the proper validation of the models in virtual screening conditions is often neglected. No analysis of the diversity of the ensemble members is performed frequently or no considerations regarding the applicability domain of the base models are being made. Methods: In this research, we review basic concepts and definitions related to virtual screening. We comment recent applications of ensemble methods to ligand-based virtual screening and highlight their advantages and limitations. Results: Next, we propose a method based on genetic algorithms optimization for the generation of virtual screening tailored ensembles which address the previously identified problems in the current applications of ensemble methods to virtual screening. Conclusion: Finally, the proposed methodology is successfully applied to the generation of ensemble models for the ligand-based virtual screening of dual target A2A adenosine receptor antagonists and MAO-B inhibitors as potential Parkinson’s disease therapeutics.

The ascent of polypharmacology in drug development has many implications for disease therapy, most notably in the efforts of drug discovery, drug repositioning, precision medicine and combination therapy. The single- target approach to drug development has encountered difficulties in predicting drugs that are both clinically efficacious and avoid toxicity. By contrast, polypharmacology offers the possibility of a controlled distribution of effects on a biological system. This review addresses possibilities and bottlenecks in the efficient computational application of polypharmacology. The two major areas we address are the discovery and prediction of multiple protein targets using the tools of computer-aided drug design, and the use of these protein targets in predicting therapeutic potential in the context of biological networks. The successful application of polypharmacology to systems biology and pharmacology has the potential to markedly accelerate the pace of development of novel therapies for multiple diseases, and has implications for the intellectual property landscape, likely requiring targeted changes in patent law.

Background: Traditional drug discovery approaches focus on a limited set of target molecules for treatment against specific indications/diseases. However, drug absorption, dispersion, metabolism, and excretion (ADME) involve interactions with multiple protein systems. Drugs approved for particular indication(s) may be repurposed as novel therapeutics for others. The severely declining rate of discovery and increasing costs of new drugs illustrate the limitations of the traditional reductionist paradigm in drug discovery. Methods: We developed the Computational Analysis of Novel Drug Opportunities (CANDO) platform based on a hypothesis that drugs function by interacting with multiple protein targets to create a molecular interaction signature that can be exploited for therapeutic repurposing and discovery. We compiled a library of compounds that are human ingestible with minimal side effects, followed by an ‘all-compounds’ vs ‘all-proteins’ fragment-based multitarget docking with dynamics screen to construct compound-proteome interaction matrices that were then analyzed to determine similarity of drug behavior. The proteomic signature similarity of drugs is then ranked to make putative drug predictions for all indications in a shotgun manner. Results: We have previously applied this platform with success in both retrospective benchmarking and prospective validation, and to understand the effect of druggable protein classes on repurposing accuracy. Here we use the CANDO platform to analyze and determine the contribution of multitargeting (polypharmacology) to drug repurposing benchmarking accuracy. Taken together with the previous work, our results indicate that a large number of protein structures with diverse fold space and a specific polypharmacological interactome is necessary for accurate drug predictions using our proteomic and evolutionary drug discovery and repurposing platform. Conclusion: These results have implications for future drug development and repurposing in the context of polypharmacology.

Background: Drug repositioning aims to identify novel indications for existing drugs. One approach to repositioning exploits shared binding sites between the drug targets and other proteins. Here, we review the principle and algorithms of such target hopping and illustrate them in Chagas disease, an in Latin America widely spread, but neglected disease. Conclusion: We demonstrate how target hopping recovers known treatments for Chagas disease and predicts novel drugs, such as the antiviral foscarnet, which we predict to target Farnesyl Pyrophosphate Synthase in Trypanosoma cruzi, the causative agent of Chagas disease.

Background: Diseases perceived as neglected tropical infections are generally caused by parasites which reach poor, underserved populations (primarily infrastructure), cause serious damage to health, and many deaths. AIDS and tuberculosis, (although not classified as neglected by WHO), are discriminated against infections which cause great social damage. The drugs currently used to treat these diseases do not have the desired effectiveness, enable the emergence of resistant strains, and in most cases are difficult to obtain. Few pharmaceutical companies are investing in new drug research for neglected diseases, for lack of financial return. This review reports the major neglected diseases, AIDS, tuberculosis, their targets, and research on multi-target drugs. Methods: The studies for new drugs against these infections involve in silico methods, synthesis, structural determinations, analytical analysis and other experimental assays. Results: A new single compound, forecasting possible pharmacodynamic and pharmacokinetic interactions becomes a simpler process; it is also believed that these drugs are safer and more efficient, since they act with synergism on different targets. It occurs but the emergence of new resistant strains and side effects. Conclusion: Multi-target drugs represent a new alternative to find new lead compounds. A ligand that targets two or more receivers may be seen as a potential drug, combating infection by different routes.

Background: In contrast to the one target-one drug paradigm, multi-target agents seem as a promising alternative to manage complex disorders and health conditions linked to drug resistance issues. In fact, many longstanding drugs are in fact unintended multi-functional therapeutics that have emerged from phenotypic screening. The last two decades, however, have witnessed the emergence of tailored multi-target agents, which according to our perspective combine the best aspects of target-based and phenotypic-based drug discovery. Methods: We discuss a number of considerations related to the design, screening and computer-aided discovery of multi-targeted drugs, along with overlooked advantages that this type of agents might have in clinical trials. A theoretic example is included to explain the reduced positive predictive value in virtual screening campaigns focused on multi-target agents. Conclusion: Multi-target agents present great therapeutic potential for the treatment of complex health conditions and the solution of drug resistance phenomena. However, they are certainly challenging for computer-aided drug discovery approaches. Merged or overlapping pharmacophores should be preferred whenever possible. It is thus suggested to perform a careful selection of the combination of pursued targets, preferring target combinations supported by co-evolution or similar biding sites.

Background: The complexity of diseases has led to recent interest in polypharmacology, which suggests that many effective drugs specially modulate multiple targets. Drugs with multiple targets can provide a superior therapeutic effect and decrease in side effect profile compared to ligands with single target, especially in the treatment of complex diseases, such as tumors, nervous system diseases and inflammatory diseases. The network-based polypharmacology holds the promise of expanding the opportunity for novel targets and drug identification. However, it faces considerable challenges to how multi-target drugs can be rationally designed from the network pharmacology perspective, particularly for combinations of targets that are structurally divergent. Methods: In this review, we focus on the pharmacological properties of current polypharmacology, discuss potential novel drug indication arising from drug repurposing, and introduce approaches to the rational design of multi-target drugs. Results: As a result, we highlighted the features of polypharmacology. Also, we have presented some computational methods to predict the potential novel multi-target drugs with lower toxicity and higher efficacy. Moreover, network analysis might play important role in repositioning drugs that modulate targets involved in different pathologies. Conclusion: This perspective aims to provide a global view on polypharmacology, which is the foundation of the next paradigm in drug discovery.

Background: Polypharmacology plays an important role in drug discovery. Polypharmacology drugs strategy provides a novel way in drug design. However, to develop a polypharmacology drug with desired profile remains a challenge. Methods: Owing to the huge progress in computational biology and chemistry, the rational drug design is becoming increasingly important in discovery of polypharmacology drug. Results: Several methodologies on the rational polypharmacology drug design have been developed, which are summarized and classified as ligand based design in polypharmacology, target based design in polypharmacology, and the hybrid of ligand and target based design in polypharmacology. Conclusion: We give an overview of the importance of polypharmacology in drug design and current trends in rational design of polypharmacology, which may be beneficial to the design and development of polypharmacology drugs.

Background: Most drugs exert their biological and physiological effects via binding to protein targets. Although drugs are traditionally optimized against a single protein, most marketed drugs exhibit clinically relevant polypharmacology – the activity of drugs at multiple targets. The wide-spread presence of polypharmacology makes it challenging to assess the mechanisms of action of multi-target drugs. Methods: This paper first reviews approaches for discovering multi-targets of drug molecules, then discusses key characteristics of label-free cell phenotypic assays, and finally focuses on how to use these assays to assess drug polypharmacology. Results: labelfree cell phenotypic assays have ability to provide a holistic view of drug action in living cells with wide phenotype/ target/pathway coverage, and permit effective deconvolution of the action of multi-target drugs at the whole cell level. Conclusion: Label-free cell phenotypic assays hold great potential in assessing drug polypharmacology.

Background: Privileged structures are potentially able to bind to a diverse range of biologically important proteins with high affinities, thus benefiting the discovery of novel bioactive compounds. 1,2-Benxisoxazole derivatives can be such important types of “privileged structures” possessing a rich diversity of biological properties especially in the area of CNS disorders. Methods: This review seeks to explore the most significant examples of 1,2-benzisoxazoles as privileged structures in terms of polypharmacology at the molecular level, specifically focusing on four 1,2-benzisoxazoles (zonisamide, risperidone, paliperidone, and iloperidone) which have been in clinical use and established as effective therapeutics. Furthermore, an updated and detailed account of the pharmacological properties of 1,2-benzisoxazole derivatives as therapeutics for CNS disorders is described. And finally, outlooks on current issues and future directions in this field are also provided. Results: 1,2-Benzisoxazole was successfully employed in the discovery and development of zonisamide for the treatment of epilepsy and Parkinson’s disease. 1,2- Benzisoxazole is also a significantly important structure for the development of atypical antipsychotics. Conclusion: It is very reasonable to say that 1,2-benzisoxazole is a good example of a privileged structure because it forms the centerpiece of small molecule chemical entities with a wide range of pharmacological properties, especially in the area of CNS disorders.

Epilepsy is a complex neurological disorder which has plagued the human population through the ages and continues to affect about 50 million people worldwide. A better understanding of the pathogenesis of epilepsy unmasks various molecular targets for the treatment of epilepsy. The currently used antiepileptic drugs (AEDs) predominately target voltage-gated ion channels (Na+γ, Ca2+γ and K+γ), GABAA receptor, glutamate receptor, synaptic vesicle 2A (SV2A) protein and carbonic anhydrase (CA). One group of AEDs acts on a single target while another group acts via multiple targets to control seizure episodes. AEDs which act via multiple mechanisms or polypharmacological mechanisms of action have appeared as broad spectrum anticonvulsant agent and therefore, they provide a better choice to clinicians to manage drug-resistant epilepsies and various other epileptic syndromes. For example, polypharmacological AEDs such as PB, VPA, OXC, FBM etc. are vital for managing epilepsy successfully, since decades. In literature there is no review available which exclusively highlights the polypharmacological mechanisms of action of existing AEDs as well as new emerging molecules. This review covers running marketed AEDs, clinical trial drugs as well as potent preclinical molecules which displayed anti-epileptic activity via multiple mechanisms of action and this appraisal will surely provide a base for discovering potent multi-targeted AEDs.

Background: The interactions of Epidermal Growth Factor Receptor (EGFR) and topoisomerases have been seen in various cancer including brain, breast, ovarian, colorectal, gastric, etc. Methods: The studies in adenocarcinoma patients, chromogenic in situ hybridization, western blotting, receptor binding assay and electromobility shift assays, etc. threw light on the biophysical and biochemical features of EGFR and Topoisomerase cross-talks. Results: It has been revealed that both the isomers of topoisomerase (Topo I and Topo II) interact via different mechanisms with EGFR. Topo II and HER2 share the same location i.e. 17q12–21 regions which could be a possible cause of predominant interactions seen between them. Topo I and EGFR interactions are mechanically related to the nucleolar translocation of heparenase by EGF and c-Jun. Conclusion: We compiled literature findings including the mechanistic interventions, signaling pathways, patents, in vitro and in vivo data of tested inhibitors and combinations in clinical trials, which provide convincing confirmations for the interactions of EGFR and topoisomerases. These interactions may be used for deriving a consistent route of mechanism, design and development of standard drug combinations and dual or multi inhibitors.

Background: β-Caryophyllene (BCP) is a natural bicyclic sesquiterpene abundantly found in essential oils from various spices, fruits and medicinal as well as ornamental plants. It is approved by United States Food and Drug Administration and European agencies as food additive, taste enhancer and flavoring agent and termed as a phytocannabinoid. Methods: All the available literature on BCP and its synonyms were collected through different literature databases. Results: BCP was found to elicit a full agonist action on cannabinoid type 2 (CB2) receptors, a G-protein coupled receptor representing important therapeutic target in several diseases. Activation of CB2 receptors notably appeared devoid of psychotropic adverse effect of cannabinoids contrary to the CB1 receptors. In addition, it activates peroxisome proliferated activator receptors (PPARs) isoforms; PPAR-α &-γ and inhibits pathways triggered by the activation of toll like receptor complex; CD14/TLR4/MD2, reduce immuneinflammatory processes and exhibit synergy with μ-opioid receptor dependent pathways. Additionally, it found as potent antagonist of homomeric nicotinic acetylcholine receptors (α7-nAChRs) and devoid of effects mediated by serotonergic and GABAergic receptors. It also modulates numerous molecular targets by altering their gene expression, signaling pathways or through direct interaction. Various pharmacological activities such as cardioprotective, hepatoprotective, gastroprotective, neuroprotective, nephroprotective, antioxidant, anti-inflammatory, antimicrobial and immune-modulator have been reported in experimental studies. It has shown potent therapeutic promise in neuropathic pain, neurodegenerative and metabolic diseases. Conclusion: The present review provides a comprehensive insight of pharmacological and therapeutic potential of BCP, its molecular mechanism and signaling pathways in different pathological conditions. The review also examines the possibility of its further development as a novel candidate for various pathologies considering the polypharmacological and multifaceted therapeutic properties potential along with favorable oral bioavailability, lipophilicity and physicochemical properties.

Background: The imidazole nucleus is inimitable and ubiquitous and it is very well known to play an important role in living organisms. Imidazole derivatives are under intensive scientific exploration due to their diverse and significant pharmacological activities. Methods: The present paper is an attempt to discuss chemistry, synthetic aspects including click chemistry procedures of imidazoles through systematic literature survey. Results: Biological activity profiles of the imidazole derivatives reported in recent scientific literature from 2000 to 2015 have been discussed in detail. It has been found that imidazole derivatives depict appreciable antiinfective activity potential. Conclusion: It is anticipated that the information compiled in this paper will be useful and motivating to prospective researchers working on this heterocylic scaffold.